Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, with the exception of the topoisomerase I inhibitor SN-38. The parallel screening of kinase inhibitors revealed that mouse and human neutrophil viability is dependent on cyclin-dependent kinase (CDK) activity but surprisingly only partially dependent on PI3 kinase and JAK/STAT signaling, revealing dominant pathways contributing to neutrophil viability. Mcl-1 haploinsufficiency sensitized neutrophils to CDK inhibition, demonstrating that Mcl-1 is a direct target for CDK inhibitors. This study reveals a therapeutic window for the kinase inhibitors BEZ235, BMS-3, AZD7762, and (R)-BI-2536 to induce apoptosis of leukemia cell lines whilst maintaining immunocompetence and hemostasis.
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PMID:Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia. 2893 29

Objective Multiple myeloma (MM) is the second most common hematological cancer. An attempt to treat MM using a topoisomerase I inhibitor was made based on our previous non-clinical studies suggesting the usefulness of an SN-38 derivative. Our aim was to conduct a phase I/II study of NK012, a micelle-forming SN-38 conjugate, in patients with relapsed/refractory multiple myeloma (RRMM). Methods NK012 was administered at doses of 12-24 mg/m2 and the safety, pharmacokinetics and preliminary efficacy were evaluated. Results Neutropenia was the most common grade 3 or 4 adverse drug reaction. Grade 4 neutropenia accounted for the majority of dose-limiting toxicities and only appeared at a dose of 24 mg/m2. The maximum concentrations and the area under the concentration-time curves from time zero to infinity for both NK012 and its active metabolite SN-38 increased in a dose-dependent manner. The best overall response was stable disease, which was achieved in 12 out of 16 patients. Conclusion The recommended dose of NK012 monotherapy for RRMM patients was concluded to be 20 mg/m2. However, this phase I/II study was terminated at the end of the phase I stage because no patients showed an objective response. Additional clinical studies of combination therapy with NK012 and other agents are warranted.
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PMID:A Phase I/II Study for Dose-finding, and to Investigate the Safety, Pharmacokinetics and Preliminary Efficacy of NK012, an SN-38-Incorporating Macromolecular Polymeric Micelle, in Patients with Multiple Myeloma. 2922 63


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